Aged circulating CD8+ T cells and their secreted factors drive cognitive decline.

Changes in peripheral CD8+ T cells are a hallmark of immune aging. However, the role of aged non-infiltrating CD8+ T cells in brain aging remains to be fully defined. Here, we showed that aged circulating CD8+ T cells and their secreted factors drove hippocampal-dependent cognitive decline. Using heterochronic parabiosis and transcriptomics analysis, we observed that peripheral CD8+ T cells maintained properties intrinsic to their age. Systemic exposure of young mice to aged CD8+ T cells elicited synaptic-related hippocampal changes and impaired cognition, and inhibiting activation, but not infiltration, mitigated their pro-aging effects. Conversely, targeting aged circulating CD8+ T cells restored youthful signatures and rescued cognition. Mechanistically, we identified granzyme K (GZMK) as a secreted pro-aging CD8+ T cell-derived factor in plasma, and GZMK inhibition rescued cognition in aged animals. Together, our data identified activated aged CD8+ T cell-derived circulating factors as potential therapeutic targets to rescue cognition in old age.